The new research method sheds light on the changes that occur in our brains as we learn

LAJOEA, Calif.
— Scientists at the Scripps Research Center have developed a new tool to monitor brain plasticity — how our brains
reshape and our bodies adapt when we learn and experience things, from watching a movie to learning a new song or a language.
Their approach, which measures proteins produced by different types of brain cells, has the potential to answer fundamental questions about how the brain works and shed light on many brain diseases
that cause errors in brain plasticity.

Previous experiments in several labs have revealed how brain activity stimulates changes in neuronal gene expression, an early step in
plasticity.
The team's experiment, published Sept.
7 in the Journal of Neuroscience, focuses on studying the next crucial step in plasticity, which is to convert the genetic code into proteins
.

Dr Hollis Klein, Professor Hahn of the Scripps Institute, chair of neuroscience and senior author of the new study, said: "We still don't understand all the underlying mechanisms of how brain cells respond to changes in response to experiences, but this approach provides a new window
into our understanding of the process.
"

When you learn something new, two things happen: First, neurons immediately transmit electrical signals
along new routes in the brain.
Then, over time, this leads to changes
in the physical structure of cells in the brain and their connections.
But scientists have always wondered what happened
between these two steps.
How does this electrical activity in neurons ultimately lead the brain to change in a more persistent way? Even further, how and why does this plasticity diminish with age and certain diseases?

Previously, researchers have studied how genes in neurons turn on and off with brain activity, hoping to gain insight into plasticity
.
With the advent of high-throughput gene sequencing technology, it has become relatively easy
to track genes in this way.
But the levels of most of these genes that code for proteins, the true workhorses of cells, are harder to monitor
.
But Klein worked closely with Scripps Professor Dr.
John Yates III and Associate Professor Dr.
Anton Maksimov to see first-hand how proteins change in the brain
.

"We wanted to dig deeper and see which proteins are important
for brain plasticity," Klein said.

The team designed a system in which they could introduce a specially labeled amino acid, one of the building blocks of a protein, into one type of neuron
at a time.
When cells produce new proteins, they incorporate this amino acid, azidoleucine, into their structure
.
Over time, by tracking which proteins contain azide leucine, researchers can monitor newly synthesized proteins and distinguish them from existing ones
.

Klein's team used azido leucine to track which proteins were produced after mice experienced large and widespread spikes in brain activity, mimicking what happens
on a small scale as we experience the world around us.
The team focused on cortical glutamatergic neurons, a type of brain cell
that processes sensory information.

After the increase in neural activity, the researchers found that the levels of 300 different proteins in neurons changed
.
Two-thirds increase at peak brain activity, and the remaining one-third decrease
in synthesis.
By analyzing the role of these so-called "candidate plasticity proteins," Cline and her colleagues were able to gain a rough idea
of how they affect plasticity.
For example, many proteins are related to the structure and shape of neurons, as well as to how neurons communicate with other cells
.
These proteins suggest that brain activity can immediately begin to affect the connections
between cells.

In addition, many proteins are related to the way DNA is packaged within cells; Changing this packaging can alter the genes
that cells can access and use over a long period of time.
This suggests that very short spikes in brain activity can lead to more lasting brain remodeling
.

"It's a clear mechanism by which changes in brain activity can cause fluctuations in gene expression to last for many days
," Klein said.

The researchers hope to use this approach to discover and study additional candidate plasticity proteins, such as proteins
that may change in different types of brain cells after animals see new visual stimuli.
Klein said their tool could also provide insight into brain disease and aging
by comparing the effects of brain activity on protein production in young and old, healthy and diseased brains.

In addition to Cline, Yates, and Maximov, authors of "Activity-inducing corticoglutamatergic neuronal neonating proteins," they include Lucio Schiapparelli, Yi Xie, Pranav Sharma, Daniel McClatchy, and Yuanhui Ma
of the Scripps Institute.

This study was supported by the National Institutes of Health (R01-EY-011261, R01-EY-027437, P30-EY-019005, R01-MH-103134, R01-EY-031597, p41-ge-103533, R01-MH-067880, U01-EY-027261, MH-118442 and NS-087026), the Hahn Family Foundation and Harold L.
Funding
from the Doerris Center for Neuroscience endowment.

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